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US 7,022,500 B1Granted
Humanized immunoglobulins
AssigneeProtein Design Labs, Inc.
InventorsCary L. Queen, Harold E. Selick
Life of this patent
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AssigneeProtein Design Labs, Inc.
InventorsCary L. Queen, Harold E. Selick
Estimating the term…
Novel methods for producing, and compositions of, humanized immunoglobulins having one or more complementarity determining regions (CDR's) and possible additional amino acids from a donor immunoglobulin and a framework region from an accepting human immunoglobulin are provided. Each humanized immunoglobulin chain will usually comprise, in addition to the CDR's, amino acids from the donor immunoglobulin framework that are, e.g., capable of interacting with the CDR's to effect binding affinity, such as one or more amino acids which are immediately adjacent to a CDR in the donor immunoglobulin or those within about about 3Å as predicted by molecular modeling. The heavy and light chains may each be designed by using any one or all of various position criteria. When combined into an intact antibody, the humanized immunoglobulins of the present invention will be substantially non-immunogenic in humans and retain substantially the same affinity as the donor immunoglobulin to the antigen, such as a protein or other compound containing an epitope.
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises at least three amino acids from the donor immunoglobulin heavy chain framework outside the Kabat and Chothia CDRs that replace the corresponding amino acids in the acceptor immunoglobulin heavy chain framework, wherein each of these at least three donor amino acids:
A humanized immunoglobulin having a complementarity determining region from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises at least three amino acids from the donor immunoglobulin heavy chain framework outside the Kabat and Chothia CDRs that replace the corresponding amino acids in the acceptor immunoglobulin heavy chain framework, wherein each of these at least three donor amino acids:
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises at least three amino acids from the donor immunoglobulin heavy chain framework outside the Kabat and Chothia CDRs that replace the corresponding amino acids in the acceptor immunoglobulin heavy chain framework, and each of these said donor amino acids:
A humanized immunoglobulin comprising a complementarity determining region from a donor immunoglobulin and heavy and light chain acceptor immunoglobulin variable region frameworks, which humanized immunoglobin in specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein the heavy and light chain acceptor immunoglobin variable region frameworks are consensus frameworks from many human antibodies, and wherein said humanized immunoglobulin comprises amino acids from the donor immunoglobulin variable region framework outside the CDRs that replace the corresponding amino acids in the one or both of the heavy and light chain acceptor immunoglobulin variable region frameworks, wherein each of these said donor amino acids is capable of interacting with the CDRs.
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein the acceptor immunoglobulin heavy chain variable region framework is a consensus of human immunoglobulin heavy chain variable region frameworks, and wherein said humanized immunoglobulin heavy chain comprises amino acids from the donor immunoglobulin framework outside the CDRs that replace the corresponding amino acids in the acceptor immunoglobulin framework, wherein each of these said donor amino acids is capable of interacting with the CDRs.
A method of producing a humanized immunoglobulin that specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, comprising the steps of
A method of producing a humanized immunoglobulin that specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, the method comprising:
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises an amino acid from the donor immunoglobulin framework outside the CDRs that replaces the corresponding amino acid in the acceptor immunoglobulin frameworks, at a position selected from the group consisting of L9, LIO, L13, L36, L41, L42, L48, L49, L63, L70, L71, L79, L87, L106, H37, H48, H49, H66, H67, H68, H72, H79, H81, H82b, H86, H87, H89, H91, H94, H103, H104, H105 and H107, utilizing the Kabat nunbering system where the donor amino acid:
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises an amino acid from the donor immunoglobulin framework outside the CDRs that replaces the corresponding amino acid in the acceptor immunoglobulin framework, at a position where the donor amino acid:
A humanized immunoglobulin having complementarity determining regions (CDRS) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises an amino acid from the donor immunoglobulin light chain framework outside the CDRs that replaces the corresponding amino acid in the acceptor immunoglobulin light chain framework, at a position where the donor amino acid;
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein said humanized immunoglobulin comprises an amino acid from the donor immunoglobulin heavy chain framework outside the CDRs that replaces the corresponding amino acid in the acceptor immunoglobulin heavy chain framework, at a position where the donor amino acid:
A humanized immunoglobulin having complementarity determining regions (CDRs) from a donor immunoglobulin and heavy and light chain variable region frameworks from acceptor immunoglobulin heavy and light chains, which humanized immunoglobulin specifically binds to an antigen with an affinity constant within about four-fold that of the donor immunoglobulin, wherein the acceptor immunoglobulin heavy chain variable region framework is a consensus sequence of human immunoglobulin heavy chain variable region frameworks, and wherein said humanized immunoglobulin comprises an amino acid from the donor immunoglobulin framework outside the CDR that replaces the corresponding amino acid in the acceptor immunoglobulin framework, at a position in the immunoglobulins where the donor amino acid:
Dependencies are inferred from the claim text.